Page 84 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioChemistry

P1: GNH Final Pages
Encyclopedia of Physical Science and Technology EN008C-380 June 29, 2001 16:42

Lipoprotein/Cholesterol Metabolism 651

that increase or decrease the cholesterol level of a cell
will affect the rate of LDL clearance from the circula-
tion. This means that nutritional factors (proportion and
type of dietary fat), hormonal status, pharmacological fac-
tors (drugs that inhibit cholesterol synthesis), and agents
that affect bile acid metabolism all affect plasma choles-
terol by influencing the level of expression of the LDL
receptor.

VIII. FAMILIAL HYPERCHOLESTEROLEMIA

Brown and Goldstein studied LDL metabolism in cells
from patients with a common metabolic inherited disor- FIGURE 9 Kinetic mechanism for LDL overproduction in familial
der called familial hypercholesterolemia (FH). People ho- hypercholesterolemia. VLDL catabolism gives rise to IDL. IDL has
mozygousforthismutationhavea6-tol0-foldelevationof two competing fates. It can be cleared by the liver or continue to be
LDL levels, are born with detectable atherosclerosis, and processed to become LDL. In the absence of the LDL receptor, IDL
clearance is sluggish, thus a large proportion of IDL is converted
usually do not survive childhood without a myocardial in-
to LDL.
farction. Heterozygotes have two- to fourfold elevations in
LDL and suffer from coronary heart disease (CHD) during
ulated by steroid hormones, nuclear transcription factors
middle age (85% of FH heterozygotes have a heart attack
bind to DNA sequences upstream from the reductase gene
before the age of 60.) FH is the most common inherited
and regulate transcription. In addition to transcriptional
metabolic disorder in humans, with a gene frequency of 1
regulation, cholesterol and certain other sterols diminish
in 500, i.e., 1 in 500 people is a heterozygote for FH.
HMG-CoA reductase by a second mechanism; they hasten
Brown and Goldstein discovered that FH cells from ho-
the degradation of the enzyme. The protein is located at the
mozygote donors showed little or no LDL-binding activ-
ity. FH cells from heterozygotes possessed about 50% of
normal activity. They concluded that mutations in the gene
encoding the LDL receptor are the molecular basis for the
FH disease. The inability to clear LDL through the nor-
mal LDL receptor pathway causes hypercholesterolemia
atherosclerosis.
The loss of LDL receptor activity readily explains the
inefficient clearance of LDL and the hypercholesterolemia
of FH patients (Fig. 9). In addition to defective catabolism
of LDL, there is also LDL overproduction for the fol-
lowing reason. IDL is also cleared through the LDL re-
ceptor. Diminished LDL receptor activity leads to pro-
longed circulation of IDL, giving it a greater opportunity
to be converted to LDL. IDL is at an important branch
point in lipoprotein metabolism; it can be directly cleared
from the circulation or it can be further processed to be-
come LDL. The LDL receptor can also regulate the se-
cretion of VLDL. It promotes reuptake of newly secreted
VLDL. Also, within the secretory pathway, the LDL re-
FIGURE 10 Regulated steps in cholesterol synthesis pathway.
ceptor promotes the degradation of newly synthesized
Step 1 is catalyzed by cytosolic acetoacetyl-CoA synthase.
apo-B100. Steps 2 and 3 are catalyzed by HMG-CoA synthase and HMG-
The principal regulatory site in the cholesterol biosyn- CoA reductase, respectively. The later two enzymes are tran-
thetic pathway is the step catalyzed by the enzyme scriptionally regulated by SREBP. Cholesterol feeds back on its
3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA own synthesis by decreasing the abundance of enzymes 2 and
3. HMG-CoA reductase is the target of widely used cholesterol-
reductase; Fig. 10). Regulation of HMG-CoA reductase
lowering drugs known as “statins.” Between mevalonate and
by LDL cholesterol occurs principally through the regu- cholesterol are more than 30 steps and branch points to nons-
lation of the level of its mRNA. In analogy to genes reg- teroidal isoprenoid molecules.